A New Role for the Aldosterone/Mineralocorticoid Receptor Pathway in the Development of Mitral Valve Prolapse.
Fiche publication
Date publication
avril 2020
Journal
Circulation research
Auteurs
Membres identifiés du Cancéropôle Est :
Pr ROSSIGNOL Patrick
Tous les auteurs :
Ibarrola J, Garcia-Peña A, Matilla L, Bonnard B, Sádaba R, Arrieta V, Alvarez V, Fernández-Celis A, Gainza A, Navarro A, Alvarez de la Rosa D, Rossignol P, Jaisser F, López-Andrés N
Lien Pubmed
Résumé
Mitral valve prolapse (MVP) is one of the most common valvular disorders. However, the molecular and cellular mechanisms involved in fibromyxomatous changes in the mitral leaflet tissue have not been elucidated. Aldosterone (Aldo) promotes fibrosis in myocardium and mineralocorticoid receptor antagonists (MRAs) improve cardiac function by decreasing cardiac fibrosis. We investigated the role of the Aldo/MR in the fibromyxomatous modifications associated with MVP. Aldo enhanced valvular interstitial cell (VIC) activation markers and induced endothelial-mesenchymal transition (EndMT) in valvular endothelial cells (VECs), resulting in increased proteoglycan secretion. MRA blocked all the above effects. Cytokine arrays showed cardiotrophin-1 (CT-1) to be a mediator of Aldo-induced VIC activation and proteoglycan secretion and CD14 to be a mediator of Aldo-induced EndMT and proteoglycan secretion in VECs. In an experimental mouse model of MVP generated by Nordexfenfluramine (NDF) administration, MRA treatment reduced mitral-valve thickness and proteoglycan content. Endothelial-specific MR deletion prevented fibromyxomatous changes induced by NDF administration. Moreover, proteoglycan expression was slightly lower in the mitral valves of MVP patients treated with MRA. These findings demonstrate, for the first time, that the Aldo/MR pathway regulates the phenotypic, molecular, and histological changes of VICs and VECs associated with MVP development. MRA treatment appears to be a promising option to reduce fibromyxomatous alterations in MVP.
Mots clés
mineralocorticoid receptor
Référence
Circ. Res.. 2020 Apr 24;: